Poisoning with organophosphates presents a problem for agricultural workers that must be exposed to some agricultural chemicals and to military personnel exposed to chemicals used in chemical warfare. Furthermore the stock-piling of organophosphates has resulted in need to find ways to detoxify such stocks, including decontamination of land where OP's have been stored.
Present treatment for poisoning by organophosphates (OP) consists of a combination of drugs such as carbamates (e.g., pyridostigmine), anti-muscarinic (e.g., atropine), and reactivators (e.g., 2-[hydroxyiminomethyl]-1-methylpyridinium chloride, pralidoxime chloride) administered in post-exposure modalities. Although this drug regimen is effective in protecting experimental animals against lethality by OP poisoning, it is not effective in preventing convulsions, performance deficits, or permanent brain damage. To alleviate these post-exposure symptoms, the use of cholinesterases (ChEs) as a pretreatment drug was successfully tested in animals including non-human primates for the sequestration of highly toxic OP anti-ChEs before they reach their physiological targets. For example, pretreatment of rhesus monkeys with FBS AChE or horse serum butyrylcholinesterase protected them against a challenge up to 5 LD.sub.50 of O-pinacolyl methylphosphonofluoridate (soman), a highly toxic OP. These monkeys pretreated with FBS AChE were devoid of any behavioral incapacitation after soman challenge, as measured by the serial probe recognition task or the primate equilibrium platform performance task. In vivo and in vitro titration of ChEs with a variety of OPs produce a 1:1 stoichiometry between organophosphate inhibited enzymes and the cumulative dose of the toxic nerve agent. These results substantiated the hypothesis that exogenously administered ChEs can effectively sequester in vivo OPs before they reach their physiological targets.
Although the use of cholinesterases as a single pretreatment drug for highly potent OPs is sufficient to provide complete protection without the need for postexposure treatment, its practical use at the present time may be limited. Large quantities of enzymes will be required to provide sufficient protection due to 1:1 stoichiometry (i.e., a single turnover) between OP and enzyme required to provide protection.
Various approaches have been considered for improving the efficacy of ChEs as pretreatment drugs. First, production of catalytic antibodies that hydrolyze OPs has been attempted. The second approach is the use of hydrolytic enzymes such as OP hydrolases. Parathion hydrolase from bacteria was shown to hydrolyze tabun with a sufficient rate to be useful as a pretreatment drug but it has a very short half-life in mice, but did provide protection from soman at dosage of 2 LD.sub.50.